Chimeric antigen receptor-induced antigen loss protects CD5.CART cells from fratricide without compromising on-target cytotoxicity.

Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5+ T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity.

CAR T Cells in T Cell Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Chimeric antigen receptor (CAR T) therapy produced excellent activity in patients with relapsed/refractory B-lineage malignancies. However, extending these therapies to T cell cancers requires overcoming unique challenges. In the recent years, multiple approaches have been developed in preclinical models and some were tested in clinical trials in patients with treatment-refractory T-cell malignanices with promising early results. Here, we review main hurdles impeding the success of CAR T therapy in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), discuss potential solutions, and summarize recent progress in both preclinical and clinical development of CAR T therapy for these diseases.